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Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models
Tomonaga Ameku1, Daisuke Taura2, Masakatsu Sone2
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Insights
Matrix metalloproteinase (MMP) 1 may be a novel risk factor for intracranial aneurysms in autosomal dominant polycystic kidney disease (ADPKD). Elevated MMP1 levels in ADPKD patients with intracranial aneurysms suggest a potential diagnostic marker.
Area of Science:
- Nephrology
- Cardiology
- Genetics
Background:
- Cardiovascular complications, particularly intracranial aneurysms (ICAs), are a leading cause of mortality in autosomal dominant polycystic kidney disease (ADPKD).
- Current diagnostic and therapeutic strategies for ICAs in ADPKD patients remain underdeveloped.
- Investigating the molecular mechanisms underlying ICAs in ADPKD is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the potential role of matrix metalloproteinase 1 (MMP1) in the development of intracranial aneurysms (ICAs) in patients with autosomal dominant polycystic kidney disease (ADPKD).
- To establish and utilize induced pluripotent stem cells (iPSCs) from ADPKD patients to model disease-specific vascular alterations.
- To identify novel biomarkers and risk factors associated with ICAs in the ADPKD population.
Main Methods:
- Generation of induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with a history of ICAs.
- Differentiation of ADPKD-iPSCs into vascular cells to analyze calcium (Ca2+) entry and gene expression profiles.
- Quantification of matrix metalloproteinase 1 (MMP1) expression in iPSC-derived endothelial cells and serum samples from ADPKD patients.
Main Results:
- Vascular cells derived from ADPKD-iPSCs exhibited distinct Ca2+ entry and gene expression patterns compared to controls.
- Specifically elevated expression of the matrix metalloproteinase 1 (MMP1) gene was observed in iPSC-derived endothelial cells from ADPKD patients with ICAs.
- A significant correlation was confirmed between elevated serum MMP1 levels and the presence of ICAs in a cohort of 354 ADPKD patients.
Conclusions:
- Elevated serum MMP1 levels represent a potential novel risk factor for the development of intracranial aneurysms in autosomal dominant polycystic kidney disease.
- ADPKD-specific iPSC-derived cellular models are valuable tools for elucidating disease mechanisms and identifying novel disease-associated molecules.
- Further research into MMP1's role could lead to improved diagnostic and therapeutic strategies for ICAs in ADPKD.
Abstract:
Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca(2+) entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
